Principal Investigator (PI)
University of Minho
The Foundation is providing £360,031 in support.
Ana Ribeiro
Jorge Manuel Rolo Pedrosa
Alexandra Gabriel Fraga
Graham F. Hatfull
Tobi Elaine Nagel
-Expertise in the field of Mycobacteria drug development and the use of relevant in vitro techniques will aid in the development of a phage cocktail that is active against a panel of M. ulcerans strains.
-Access to in vitro drug combination evaluation will be key to address the interactions of phage cocktails with standard antibiotics.
-Access to flow cytometry/imaging techniques that will allow for fast screening of phages, particularly relevant for the slow growing M. ulcerans bacteria.
-Experts in in vivo PK and safety can help obtain robust results that will enable future decisions for clinical assets and FTIH.
-Access to collection of anti-mycobacterial drugs, including clarithromycin, would be very beneficial for this project.
Buruli Ulcer (BU) is a NTD caused by Mycobacterium ulcerans infection. The progression of the disease affects primarily the skin but can evolve to more severe clinical presentations as it progresses to soft tissues and bone. The exact mechanism of transmission is not yet well understood, and together with the lack of an efficacious vaccine, prevention is challenging (1).
The highest incidence occurs in children in endemic regions of sub-Saharan Africa, and the current standard treatment is 8-weeks of daily rifampicin and clarithromycin combined with wound care; though, in severe cases, surgical resection of affected area is required, often associated with debilitating sequelae.
Due to the immunosuppressive and cytopathic characteristics of mycolactone, a toxin secreted by M. ulcerans (2), wound healing is complex and susceptible to secondary infections. In rural communities where access to proper health care is limited, patient care is challenging, and even when antibiotic treatment is successful, poor wound healing often leads to disabilities and stigmatization, including social exclusion (3). Therefore, novel approaches are desperately needed.
Bacteriophages (also known as phages) are viruses that naturally kill bacteria with much higher specificity than broad spectrum antibiotics. Phages have shown efficacy in controlling infections in pre-clinical and clinical settings, and recent data have demonstrated their potential in dramatically improving wound healing when topically administered in patients with diabetic foot ulcers complicated by opportunistic infections (4).
Phage therapy is a growing novel strategy in the fight against antimicrobial resistance (AMR); however, it has yet not yet been utilized for neglected diseases that are endemic in Low- and-Middle Income Countries (LMIC). Thus, we aim to develop a phage therapeutic targeting BU. To accomplish this, we have brought together a consortium that includes leading global experts in the field of BU, phage therapy in mycobacterial infections, and also drug development for LMIC contexts.
Previous studies conducted by members of this consortium have demonstrated the therapeutic potential of a single dose of a phage in the development of BU disease: in a BU murine model, phage treatment limited the progression of ulceration and reduced bacterial infection, not only at the site of administration but also in distal areas. In those studies, phage treatment also resulted in an increase in interferon levels, which could help mitigate the immunosuppressive effect of M. ulcerans-associated mycolactone (5).
Together, these data suggest that phage-based therapy could improve the current antibiotic-based treatment for BU. If successful, this proposed project could generate novel pre-clinical candidates with the potential to radically change the prognosis of the disease, as well as the recovery and quality of life of patients in LMIC endemic regions.